Extreme clustering of type-1 NF1 deletion breakpoints co-locating with G-quadruplex forming sequences
Extreme clustering of type-1 NF1 deletion breakpoints co-locating with G-quadruplex forming sequences
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DOI：
10.1007/s00439-018-1904-1
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发表时间：
2018-07
期刊：
影响因子：
5.3
通讯作者：
Anna Summerer;V. Mautner;M. Upadhyaya;K. Claes;J. Högel;D. Cooper;L. Messiaen;H. Kehrer-Sawatzki
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文献类型：
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作者：
Anna Summerer;V. Mautner;M. Upadhyaya;K. Claes;J. Högel;D. Cooper;L. Messiaen;H. Kehrer-Sawatzki
1.4Mb的1 NF 1型缺失的断裂点位于NF 1-REPa和NF 1-REPc内，它们表现出复杂的结构，包括在直接和反向方向上的不同片段重复。在此，我们系统地评估了由非等位基因同源重组（NAHR）和其他突变机制介导的1型NF 1缺失的比例。为此，我们分析了236个NAHR 1型缺失，观察到其中179个（75.8%）的断点位于NAHR热点PRS 2内，而39个缺失（16.5%）的断点位于PRS 1内。16个缺失显示断点位于这些NAHR热点之外，但也由NAHR介导。在236例1型NF 1缺失中，有234例（99.2%）的断裂点由NAHR介导。因此，NF 1-REPa和NF 1-REPc强烈倾向于复发NAHR，这是1型NF 1缺失的主要机制。我们还观察到1型NF 1缺失断裂点和G-四链体形成序列（GQ）以及PRDM 9结合位点侧翼区域之间的非随机重叠。这些发现意味着GQ和PRDM 9结合位点有助于1型缺失断点的聚集。两种类型的序列的共定位在PRS 2内处于最高水平，表明它们对该热点内大大增加的NAHR活性的协同贡献。
The breakpoints of type-1NF1deletions encompassing 1.4-Mb are located within NF1-REPa and NF1-REPc, which exhibit a complex structure comprising different segmental duplications in direct and inverted orientation. Here, we systematically assessed the proportion of type-1NF1deletions caused by nonallelic homologous recombination (NAHR) and those mediated by other mutational mechanisms. To this end, we analyzed 236 unselected type-1 deletions and observed that 179 of them (75.8%) had breakpoints located within the NAHR hotspot PRS2, whereas 39 deletions (16.5%) had breakpoints located within PRS1. Sixteen deletions exhibited breakpoints located outside of these NAHR hotspots but were also mediated by NAHR. Taken together, the breakpoints of 234 (99.2%) of the 236 type-1NF1deletions were mediated by NAHR. Thus, NF1-REPa and NF1-REPc are strongly predisposed to recurrent NAHR, the main mechanism underlying type-1NF1deletions. We also observed a non-random overlap between type-1NF1-deletion breakpoints and G-quadruplex forming sequences (GQs) as well as regions flanking PRDM9Abinding-sites. These findings imply that GQs and PRDM9Abinding-sites contribute to the clustering of type-1 deletion breakpoints. The co-location of both types of sequence was at its highest within PRS2, indicative of their synergistic contribution to the greatly increased NAHR activity within this hotspot.